Leptospirosis, caused by infectious Leptospira, is an important zoonotic disease that affects more than 1 million people per year worldwide, especially the poor in developing countries. Case fatality rates of 5-20% are often reported with deaths mostly due to severe renal and lung complications (which are rising worldwide). As a result, there has been a recent surge in the number of sequenced leptospiral genomes and a renewed interest in dissecting mechanisms by which the bacteria cause disease. This wealth of available genomic data constitutes a superb database for better understanding Leptospira biology and improving human health. Perhaps the most telling finding arising from our recent comparisons of the gene repertoires of e300 leptospiral strains was the observation that whereas infectious Leptospira contained several genes to make their own B12 (cobalamin, Cbl), none of the non-infectious strains did. This was quite unexpected for two reasons: (i) both infectious and non-infectious varieties survive in moist soil and water (similar niches); and (ii) or almost fifty years leptospiral biologists believed the bacteria needed to be supplemented with B12 in order to survive, i.e. could not make their own. Even more intriguing, these Cbl synthesis genes were always found to be closely associated with Cbl-binding non-coding RNA elements known to regulate Cbl-synthesis genes (among others) in a number of microbes, including some vey important human pathogens. Cbl is the largest and most complex known natural organometallic cofactor and coenzyme, and its de novo synthesis involves ~30 enzyme-catalyzed reactions. Accordingly, these regulatory should contribute to fitness by modulating Cbl synthesis enzyme production in response to changes in Cbl levels, blocking Cbl synthesis when Cbl is abundant and allowing resumption of Cbl synthesis whenever exogenous Cbl is limiting. Mammals, for their part, can absorb, transport and sequester Cbl from invading pathogens, processes that involve many carrier proteins, receptors and transporters. Therefore, we hypothesize that acquisition of these Cbl-regulated genes by certain Leptospira species was critical to their evolution from solely environmental to highly infectious species. Our preliminary experiments have confirmed that pathogenic Leptospira can be maintained by serial in vitro passage for at least 6 months in the absence of exogenous Cbl, supporting our hypothesis and overall feasibility of our experiments. More generally, we anticipate that this hypothesis-driven, mechanism-oriented study will establish a critical role for Cbl autotrophy in bacterial pathogenesis, and deepen understanding of Cbl-dependent metabolism in Spirochetes, of which considerably little is known.